Safety & Efficacy of Zirconium Silicate in Chronic Kidney Disease or Moderate Kidney Dysfunction With Mild Hyperkalemia

• ClinicalTrials.gov Identifier: NCT01493024
• Recruitment Status: Completed
• First Posted: December 15, 2011
• Results First Posted: June 29, 2018
• Last Update Posted: June 29, 2018
• Sponsor: ZS Pharma, Inc.
• Information provided by (Responsible Party): ZS Pharma, Inc.

Study Description

Brief Summary:

It is hypothesized that zirconium silicate is safe and well tolerated and more effective than placebo (alternative hypothesis) in lowering serum potassium levels in subjects with serum potassium between 5 - 6.0 mmol/l versus no difference between zirconium silicate and placebo (null hypothesis). It is hypothesized that zirconium silicate even up to the top dose of 10g three times a day is well tolerated.

Condition or disease	Intervention/treatment	Phase
Hyperkalemia; Chronic Kidney Disease; Kidney Dysfunction	Drug: Zirconium silicate (ZS); Drug: Placebo	Phase 2

Detailed Description:

A total of 90 subjects with moderate CKD (defined as GFR between 40- 60ml/min) and mild hyperkalemia (S-K between 5-6 mmol/l) will be enrolled in the study where, in a double-blind dose-escalating fashion (three separate cohorts), they will be randomized to receive one of the doses of ZS (0.3g, 3g and 10g) or placebo, administered 3 times (tid) daily with meals. The first cohort will have 18 subjects while both of the second and third cohorts will have 36 subjects for a total of 90 subjects.

Safety and tolerability will be assessed by an Independent Data Safety Monitoring Board (DSMB) after completion of each cohort, before escalation to the next dose level will be allowed. The next dose escalation will happen no sooner than one week after the last dose of study drug at the previous dosing level has been administered. Safety stopping rules will be specified for this study. Within the first dose level (300 mg dose), 12 subjects will be randomized to receive ZS, whereas 6 subjects will be randomized to receive placebo for a total of 18 subjects in this first cohort. In the next two cohorts (3 g and 10 g doses), 24 subjects per cohort will be randomized to receive ZS, whereas 12 subjects per cohort will be randomized to receive placebo for a total of 36 subjects in each of the second and third cohorts.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Multicenter, Prospective, Randomized, Placebo-Controlled, Double-blind Dose Escalating Study of Safety, Tolerability and Pharmacodynamics of Zirconium Silicate in Chronic Kidney Disease and Moderate Kidney Dysfunction With Mild Hyperkalemia
• Actual Study Start Date: November 30, 2011
• Actual Primary Completion Date: May 31, 2012
• Actual Study Completion Date: June 30, 2012

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Placebo (silicified microcrystalline cellulose) randomized to mimic escalating doses of experimental drug administered three times daily (TID) with meals.	Drug: Placebo; Randomized to mimic escalating doses of experimental drug administered 3 times daily (tid) with meals.; Other Name: silicified microcrystalline cellulose
Experimental: Zirconium silicate (ZS); Randomized escalating doses (0.3g, 3g and 10g) of ZS (fractionated, protonated, microporous zirconium silicate, an oral sorbent) administered 3 times daily (tid) with meals.	Drug: Zirconium silicate (ZS); Randomized escalating doses (0.3g, 3g and 10g) of ZS (fractionated, protonated microporous Zirconium Silicate, an oral sorbent) administered 3 times daily (tid) with meals.; Other Name: ZS-9

Outcome Measures

Primary Outcome Measures :

1. Difference in the Exponential Rate of Change in Serum Potassium (S-K) Levels Versus Placebo During the Initial 48 Hours of Study Drug Treatment [ Time Frame: 24 and 48 hours post first study drug dose ]
   The rate of fall in S-K levels during the initial 48 hours of study drug treatment between the placebo treated subjects and the ZS treated subjects measured on a log scale

Secondary Outcome Measures :

1. Serum Potassium (S-K) at Individual Time Points. [ Time Frame: First 48 hours of study ]
   Serum potassium (S-K) at individual time points through Study day 3/0hour.
2. Time Specific S-K Levels to Normalization [ Time Frame: 48 and 72 hours post first study drug dose ]
   Percent of subjects achieving S-K normalization (<=as defined by S-K levels of 3.5 to 4.9 mmol/L) from baseline at Study Days 2 and 3 at 0 hr.
3. Time Specific Decreases in S-K Levels of > = 0.5 mmol/L [ Time Frame: 24 and 48 hours post first study drug dose ]
   Percentage of participants achieving a 0.5mmol/L drop from baseline at Study Days 2 and 3 at 0 hr.
4. Percentage of Participants With Normal S-K Levels at End of Study Day 2 [ Time Frame: 48 hours post first study drug dose ]
   Percentage (%) of subjects who achieve S-K normalization at end of Study Day 2
5. Urine Sodium Excretion [ Time Frame: 24 and 48 hours post first study drug dose ]
   Urine sodium excretion compared between the combined placebo-treated controls and the ZS-treated subjects (measured throughout two 24-hour periods on Study Days 1 and 2).
6. Urine Potassium Excretion [ Time Frame: 24 and 48 hours post study drug dose ]
   Urine potassium excretion compared between the combined placebo-treated controls and the ZS-treated subjects (measured throughout two 24-hour periods on Study Days 1 and 2).
7. Urea Nitrogen Excretion [ Time Frame: 24 and 48 hours post study drug dose ]
   Urea nitrogen excretion compared between the combined placebo-treated controls and the ZS-treated subjects (measured throughout two 24-hour periods on Study Days 1 and 2).
8. Blood Urea Nitrogen [ Time Frame: 24 and 48 hours post study drug dose ]
   Blood urea nitrogen compared between the combined placebo-treated controls and the ZS-treated subjects (measured 24 & 48 hours post dose on Study Days 2 and 3).
9. Serum Magnesium (S-Mg) Levels [ Time Frame: 24 and 48 hours post study drug dose ]
   Serum magnesium compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3).
10. Serum Calcium (S-Ca) Levels [ Time Frame: 24 and 48 hours post study drug dose ]
    Serum calcium compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3).
11. Serum Sodium (S-Na) Levels [ Time Frame: 24 and 48 hours post study drug dose ]
    Serum sodium compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3).
12. Serum Bicarbonate (HCO3) Levels [ Time Frame: 24 and 48 hours post study drug dose ]
    Serum bicarbonate compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3).
13. 24-hour Urinary Excretion of Potassium [ Time Frame: 24 and 48 hours post study drug dose ]
    24-hour urinary excretion of potassium on Study Days 1 and Day 2
14. 24-hour Urinary Excretion of Sodium [ Time Frame: 48 hours ]
    24-hour urinary excretion of sodium on Study Days 1 and Day 2
15. 24-hour Urinary Excretion of Urea Nitrogen [ Time Frame: 48 hours ]
    24-hour urinary excretion of urea nitrogen on Study Days 1 and Day 2
16. 24-hour Urinary Excretion of Creatinine [ Time Frame: 48 hours ]
    24-hour urinary excretion of creatinine on Study Days 1 and Day 2

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Provision of written informed consent.
• Over 18 years of age.
• GFR between 40-60 ml/min as estimated by the CKD-EPI equation. After screening two additional GFR values of between 40-60ml/min must be repeated within 24 hours before inclusion is allowed.
• S-K between 5.0 - 6.0 mmol/l (inclusive) during Study Day 0.
• Ability to have repeated blood draws or effective venous catheterization.
• Women of child bearing potential must be practicing a highly effective method of birth control.

Exclusion Criteria:

• Pseudohyperkalemia such as excessive fist clinching hemolyzed blood specimen, severe leukocytosis or thrombocytosis.
• Subjects treated with lactulose, xifaxan or other non-absorbed antibiotics for hyperammonemia within the last 7 days.
• Subjects treated with resins (such as sevelamer acetate, calcium acetate or calcium carbonate, lanthanum carbonate, Sodium polystyrene sulfonate (SPS; e.g. Kayexalate®) within the last 7 days.
• Subjects with a life expectancy of less than 3 months.
• Subjects who are HIV positive.
• Subjects who are severely physically or mentally incapacitated and who in the opinion of investigator are unable to perform the subjects' tasks associated with the protocol.
• Women who are pregnant, lactating, or planning to become pregnant.
• Subjects with Ketoacidosis/Acidemia.
• Cancer within the last 5 years (other than successfully treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or early stage prostate cancer).
• Presence of any condition which, in the opinion of the investigator, places the subject at undue risk or potentially jeopardizes the quality of the data to be generated.
• Known hypersensitivity or previous anaphylaxis to Zirconium Silicate or to components thereof.
• Subjects who have cardiac arrhythmias that require immediate treatment.
• Subjects with ECG changes associated with hyperkalemia.
• Subjects with acute kidney injury.

Contacts and Locations

Locations

United States, Arizona

Southwest Clinical Research Institute

Tempe, Arizona, United States, 85284

United States, California

West Coast Clinical Trials

Costa Mesa, California, United States, 92626

United States, Florida

Riverside Clinical Research

Edgewater, Florida, United States, 32132

Elite Research Institute, Inc.

Miami, Florida, United States, 33169

Compass Research Phase 1, LLC

Orlando, Florida, United States, 32806

Lakeview Medical Research

Summerfield, Florida, United States, 34491

United States, Kansas

Johnson County Clin-Trials

Lenexa, Kansas, United States, 66219

United States, Texas

Southwest Houston Research, Ltd

Houston, Texas, United States, 77099

Renal Associates, P.A.

San Antonio, Texas, United States, 78215

Sponsors and Collaborators

ZS Pharma, Inc.

Investigators

• Study Chair: Henrik Rasmussen, MD; ZS Pharma, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Natale P, Palmer SC, Ruospo M, Saglimbene VM, Strippoli GF. Potassium binders for chronic hyperkalaemia in people with chronic kidney disease. Cochrane Database Syst Rev. 2020 Jun 26;6:CD013165. doi: 10.1002/14651858.CD013165.pub2.

• Responsible Party: ZS Pharma, Inc.
• ClinicalTrials.gov Identifier: NCT01493024
• Other Study ID Numbers: ZS-002
• First Posted: December 15, 2011
• Results First Posted: June 29, 2018
• Last Update Posted: June 29, 2018
• Last Verified: May 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Hyperkalemia; Urologic Diseases; Water-Electrolyte Imbalance; Metabolic Diseases